Protein Structure & Function: Lecture Notes for BCB 444/544X at Iowa State University - Pr, Study notes of Bioinformatics

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Protein Structure & Function 11/04/05 D Dobbs ISU - BCB 444/544X 1 11/04/05 D Dobbs ISU - BCB 444/544X: Protein Structure & Function 1 11/4/05 Protein Structure & Function 11/04/05 D Dobbs ISU - BCB 444/544X: Protein Structure & Function 2 Announcements Exam 2 - Has been graded - Will be returned at end of class today Grade statistics - 444 Average = 81/100 544 Average = 100/118 Questions? 11/04/05 D Dobbs ISU - BCB 444/544X: Protein Structure & Function 3 Announcements BCB 544 Projects - Important Dates: Nov 2 Wed noon - Project proposals due to David/Drena Nov 4 Fri PM - Approvals/responses & tentative presentation schedule to students Dec 2 Fri noon - Written project reports due Dec 5,7,8,9 class/lab - Oral Presentations (20') (Dec 15 Thurs = Final Exam) 11/04/05 D Dobbs ISU - BCB 444/544X: Protein Structure & Function 4 Bioinformatics Seminars Nov 4 Fri 12:10 PM BCB Faculty Seminar in E164 Lago How to do sequence alignments on parallel computers Srinivas Aluru, ECprE & Chair, BCB Program http://www.bcb.iastate.edu/courses/BCB691F2005.html Next week: Nov 10 Thurs 3:40 PM ComS Seminar in 223 Atanasoff Computational Epidemiology Armin R. Mikler, Univ. North Texas http://www.cs.iastate.edu/~colloq/#t3 11/04/05 D Dobbs ISU - BCB 444/544X: Protein Structure & Function 5 Bioinformatics Seminars CORRECTION: Week after next - Baker Center/BCB Seminars: (seminar abstracts available at above link) Nov 14 Mon 1:10 PM Doug Brutlag, Stanford Discovering transcription factor binding sites Nov 15 Tues 1:10 PM Ilya Vakser, Univ Kansas Modeling protein-protein interactions both seminars will be in Howe Hall Auditorium 11/04/05 D Dobbs ISU - BCB 444/544X: Protein Structure & Function 6 RNA Structure & Function/Prediction Protein Structure & Function Mon Review - promoter prediction RNA structure & function Wed RNA structure prediction 2' & 3' structure prediction miRNA & target prediction - Lab 10 Fri - a few more words re: Algorithms Protein structure & function Protein Structure & Function 11/04/05 D Dobbs ISU - BCB 444/544X 2 11/04/05 D Dobbs ISU - BCB 444/544X: Protein Structure & Function 7 Reading Assignment (for Fri/Mon) Mount Bioinformatics • Chp 10 Protein classification & structure prediction http://www.bioinformaticsonline.org/ch/ch10/index.html • pp. 409-491 • Ck Errata: http://www.bioinformaticsonline.org/help/errata2.html Other? That should be plenty… 11/04/05 D Dobbs ISU - BCB 444/544X: Protein Structure & Function 8 Review last lecture: RNA Structure Prediction 11/04/05 D Dobbs ISU - BCB 444/544X: Protein Structure & Function 9 miRNA and RNAi pathways RISC Dicerprecursor miRNA siRNAs Dicer “translational repression” and/or mRNA degradation mRNA cleavage, degradation RNAi pathwaymicroRNA pathway MicroRNA primary transcript Exogenous dsRNA, transposon, etc. target mRNA Drosha RISC RISC C Burge 2005 11/04/05 D Dobbs ISU - BCB 444/544X: Protein Structure & Function 10 miRNA Challenges for Computational Biology • Find the genes encoding microRNAs • Predict their regulatory targets • Integrate miRNAs into gene regulatory pathways & networks Computational Prediction of MicroRNA Genes & Targets C Burge 2005 Need to modify traditional paradigm of "transcriptional control" primarily by protein-DNA interactions to include miRNA regulatory mechanisms! 11/04/05 D Dobbs ISU - BCB 444/544X: Protein Structure & Function 11 RNA structure prediction strategies 1) Energy minimization (thermodynamics) 2) Comparative sequence analysis (co-variation) 3) Combined experimental & computational Secondary structure prediction 11/04/05 D Dobbs ISU - BCB 444/544X: Protein Structure & Function 12 Secondary structure prediction strategies 1) Energy minimization (thermodynamics) • Algorithm: Dynamic programming to find high probability pairs (also, some genetic algorithms) • Software: Mfold - Zuker Vienna RNA Package - Hofacker RNAstructure - Mathews Sfold - Ding & Lawrence R Knight 2005 Protein Structure & Function 11/04/05 D Dobbs ISU - BCB 444/544X 5 11/04/05 D Dobbs ISU - BCB 444/544X: Protein Structure & Function 25 RNA Secondary structure prediction: Performance? 1) Energy minimization (via dynamic programming) 73% avg. prediction accuracy - single sequence 2) Comparative sequence analysis 97% avg. prediction accuracy - multiple sequences (e.g., highly conserved rRNAs) much lower if sequence conservation is lower &/or fewer sequences are available for alignment 3) Combined - recent developments: combine thermodynamics & co-variation & experimental constraints? IMPROVED RESULTS 11/04/05 D Dobbs ISU - BCB 444/544X: Protein Structure & Function 26 RNA structure prediction strategies Requires "craft" & significant user input & insight 1) Extensive comparative sequence analysis to predict tertiary contacts (co-variation) e.g., MANIP - Westhof 2) Use experimental data to constrain model building e.g., MC-CYM - Major 3) Homology modeling using sequence alignment & reference tertiary structure (not many of these!) 4) Low resolution molecular mechanics e.g., yammp - Harvey Tertiary structure prediction 11/04/05 D Dobbs ISU - BCB 444/544X: Protein Structure & Function 27 New Today: Protein Structure & Function 11/04/05 D Dobbs ISU - BCB 444/544X: Protein Structure & Function 28 Protein Structure & Function Protein structure - primarily determined by sequence Protein function - primarily determined by structure • Globular proteins: compact hydrophobic core & hydrophilic surface • Membrane proteins: special hydrophobic surfaces • Folded proteins are only marginally stable • Some proteins do not assume a stable "fold" until they bind to something = Intrinsically disordered  Predicting protein structure and function can be very hard -- & fun! 11/04/05 D Dobbs ISU - BCB 444/544X: Protein Structure & Function 29 4 Basic Levels of Protein Structure 11/04/05 D Dobbs ISU - BCB 444/544X: Protein Structure & Function 30 Primary & Secondary Structure Primary • Linear sequence of amino acids • Description of covalent bonds linking aa’s Secondary • Local spatial arrangement of amino acids • Description of short-range non-covalent interactions • Periodic structural patterns: α-helix, β-sheet Protein Structure & Function 11/04/05 D Dobbs ISU - BCB 444/544X 6 11/04/05 D Dobbs ISU - BCB 444/544X: Protein Structure & Function 31 Tertiary & Quaternary Structure Tertiary • Overall 3-D "fold" of a single polypeptide chain • Spatial arrangement of 2’ structural elements; packing of these into compact "domains" • Description of long-range non-covalent interactions (plus disulfide bonds) Quaternary • In proteins with > 1 polypeptide chain, spatial arrangement of subunits 11/04/05 D Dobbs ISU - BCB 444/544X: Protein Structure & Function 32 "Additional" Structural Levels • Super-secondary elements • Motifs • Domains • Foldons